5-(substituted)isoxazole compounds

ABSTRACT

A novel process for producing α-[(dialkylamino)substituted-methylene]β-oxo-(substituted) propanenitriles of the formula: ##STR1## where R, R 1  and R 2  are defined in the specification by reacting a substituted isoxazole with a diaklyamide dimethylacetal is provided.

This is a divisional of co-pending application Ser. No. 07/613,601, now U.S. Pat. No. 5,059,709 filed on Nov. 13, 1990.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to a process for the synthesis of α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile compounds and to novel substituted isoxazole compounds useful as intermediates in the process.

2. Description of the Prior Art

The α-[(dialkylamino)substituted-methylene]-β-oxo-(substituted)propanitrile compounds are important intermediates for the preparation of therapeutic aryl and heteroaryl [7-(aryl and heteroaryl)pyrazolo(1,5-a)-pyrimidin-3-yl]methanone compounds which are useful as anxiolylic, antiepileptic, sedative-hypnotic and skeletal muscle relaxant agents. The aryl and heteroaryl [7-(aryl and hetroaryl)-pyrazolo [1,5-a]pyrimidin-3-yl]methanone compounds and uses for such compounds are described in U.S. Pat. No. 4,521,422, the contents of which are incorporated by reference.

In U.S. Pat. No. 4,900,836, the contents of which are incorporated by reference, a series of reactions in which the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile compounds are utilized to produce the [7-(alkyl and hetroaryl)pyrazolo (1,5-a)-pyrimidin-3-yl]methanone compounds is described. This reference also describes the synthesis of the α-[(dialkylamino) substituted methylene]-β-oxo-(substituted) propanenitrile compounds via the reaction of a substituted acetonitrile with a dimethylformamide dimethylacetal.

It has now been found that α-[(dialkylamino) substituted methylene]β-oxo-(substituted) propane nitrile compounds may be advantageously synthesized via reaction of a substituted isoxazole with a dialkylamide dimethylacetal. The use of substituted isoxazole compounds in the production of α-[(dialkylamino)substituted methylene]-β-oxo(substituted)propanenitrile compounds has not been taught nor suggested by the art.

Certain substituted isoxazole compounds and their synthesis are known. For example, 5-(2,3,4,5-tetrafluorophenyl)-isoxazole (Chem. Abst. Registry No. 110985-65-4), 5-(2,4-dichloro-5-fluorophenyl) isoxazole (Registry No. 103318-74-6), 5-(2,3,-dichloro-phenyl) isoxazole (Registry No. 76344-98-4), 5-(5-nitro-2-furyl)-isoxazole (Registry No. 32332-91-5), 5-(4-methylphenyl)-isoxazole (Registry No. 7064-35-9), 5-(m -chloro phenyl) isoxazole (Registry No. 7064-34-8), 5-(m-bromo phenyl) isoxazole (Registry No. 7064-33-7), 5-(p-chloro-phenyl) isoxazole (Registry No. 7064-32-6), 5-(p-bromo phenyl) isoxazole (Registry No. 7064-31-5), N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-2-5-isoxazolyl)-3-thiophenesulfonamide (Registry No. 103118-33-8), 3-hydroxy-4-(5-isoxazolyl)-2(5H)-foranone (Registry No. 84-608-81-1) and 5-phenyl isoxazole (Registry No. 1006-67-3) are known. Other substituted isoxazole compounds including those claimed herein are not known.

SUMMARY OF THE INVENTION

The invention provides an improved process for the large scale production of α-[(dialkylamino)substituted-methylene]-β-oxo-(substituted)propanitrile compounds which may be represented by the following structural formula: ##STR2## wherein R is lower alkyl(C₁ -C₃); R₁ is selected from the group consisting of phenyl; phenyl substituted by one of the group selected from halogen, nitro, alkyl(C₁ -C₃) and alkoxy(C₁ -C₃); phenyl di- or tri- substituted by methoxy, halogen and lower alkyl; phenyl substituted by one of the group consisting of dialkylamino(C₁ -C₃), methylenedioxy, alkylthio(C₁ -C₃), alkylsulfonyl(C₁ -C₃), amino, alkanoyl(C₁ -C₃)amino, trifluoromethyl and phenyl; thienyl; thienyl substituted by one or two of the group selected from halogen and alkyl(C₁ -C₃); furanyl; furanyl substituted by one or two of the group selected from alkyl(C₁ -C₃), naphthalenyl, pyrazinyl, and pyrrolyl; and R₂ is selected from the group consisting of hydrogen and lower alkyl(C₁ -C₃). The improved process comprises reacting an R₁ substituted isoxazole having the formula ##STR3## wherein R₁ is as defined above with a dialkylamide dimethylacetal having the formula ##STR4## wherein R and R² are as defined above at a temperature from about 50° C. to about 100° C. and recovering the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitrile so produced. The invention also provides certain novel R₁ substituted isoxazole compounds.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The process and compounds of the present invention are described in the following reaction scheme I: ##STR5##

In accordance with the above reaction scheme a 1-(cyclicsubstituted)ethanone (1), where R₁ is as described above, is reacted with dimethylformamide dimethyl acetal (2) for 15 hours at 50°-100° C. Evaporation and recrystallization gives the 3-dimethylamino-1-(substituted)-2-propen-1-one (3).

The 3-dimethylamino-1-(substituted)-2-propen-1-one compounds (3) and their synthesis are described in greater detail in U.S. Pat. No. 4,178,449 (col 2 lines 44-54), U.S. Pat. No. 4,281,000 (col 2 lines 28-34), and U.S. Pat. No. 4,236,005 (col 2 lines 45-54).

The 3-dimethylamino-1-(substituted)-2-propen-1-one (3) is reacted with hydroxylamine hydrochloride in absolute methanol for 2 hours at a temperature from about 50° to about 100° C. The reaction solution is evaporated, dissolved in methylene chloride and passed thru hydrous magnesium silicate. Concentration of the eluate gives the desired substituted isoxazole (5) which is reacted with a dialkylamide dimethylacetal (6) at a temperature from about 50° to about 100° C. for 4 hours. The reaction solution is evaporated, dissolved in methylene chloride and passed thru hydrous magnesium silicate. On cooling and/or concentrating the methylene chloride solution, the desired α-[(dialkylamino)substituted methylene]-β-oxo-(substituted) propanenitrile (7) crystallizes.

As described in U.S. Pat. No. 4,900,836, the α-[(dialkylamino)substituted methylene]-β-oxo-(substituted)propanenitriles find utility as intermediates in the preparation of therapeutic aryl and heteroaryl[7-(aryl and heteroaryl)pyrazolo(1,5-a)pyrimidin-3-yl]methanones. As described in U.S. Pat. No. 4,521,422 the aryl and heteroaryl[7-(aryl and heteroaryl)pyrazolo(1,5-a) pyrimidin-3-yl]methanones are useful as anxiolylic, antiepileptic, sedative-hypnotic, and skeletal muscle relaxant agents.

The above described process is an improvement over the procedure described in U.S. Pat. No. 4,900,836. The 1-(cyclicsubstituted)ethanones are readily available and inexpensive; the over all yields are higher; and the reaction work-ups are less labor and time intensive.

The following non-limiting examples illustrate the process of the present invention as well as the preparation of the novel compounds isoxazole intermediates.

EXAMPLE 1 3-Dimethylamino-1-(3 thienyl)-2-propen-1-one

A mixture of 48.4 g of 3-acetylthiophene and 75 ml of dimethylformamide dimethyl acetal, under nitrogen, is heated for 15 hours on a steam bath. The reaction is concentrated in vacuo and the residue crystallized from methylene chloride/hexane to give 60.55 g (87%) of the desired product, mp 89°-90° C.

Using the general procedure of Example 1, the following compounds of Example 2-26 shown in Table 1 are prepared.

                                      TABLE I                                      __________________________________________________________________________     Example                                                                             Starting Material                                                                            Compound             MP °C.                          __________________________________________________________________________      2   Acetophenone  3-dimethylaminoacrylophenone                                                                        93.0-94°                         3   2-Acetyl-5-bromothiophene                                                                    1-(5-bromo-2-thienyl)-3-dimethylamino-2-                                                            118-120°                                           propen-1-one                                                 4   4'-Chloroacetophenone                                                                        trans-4'-chloro-3-dimethylaminoacrylo-                                                              83-84°                                             phenone                                                      5   4'-Methoxyacetophenone                                                                       3-dimethylamino-4'-methoxyacrylophenone                                                             92-95°                           6   4'-Methylacetophenone                                                                        3-dimethylamino-4'-methylacrylophenone                                                              92.5-95°                         7   2-Acety-5-methylthiopene                                                                     1-(5-methyl-2-thienyl)-3-dimethylamino-2-                                                           113-115°                                           propen-1-one                                                 8   2-Acetylfuran 3-(dimethylamino)-1-(2-furyl)-2-propen-                                                             84-86°                                             1-one                                                        9   2-Acetyl-5-methylfuran                                                                       3-(dimethylamino)-1-(5-methyl-2-furanyl)-                                                           126-128°                                           2-propen-1-one                                              10   3'-Ethylacetophenone                                                                         3-(dimethylamino)-1-(3-ethylphenyl)-2-                                                              yellow orange                                             propen-1-one         viscous liquid                         11   4'-Nitroacetophenone                                                                         3-dimethylamino-4'-nitroacrylophenone                                                               150-151°                        12   2'-Fluoroacetophenone                                                                        ( .sub.-- E)-3-dimethylamino-2'-fluoroacrylophenone                                                 yellow oil                             13   4'-Fluoroacetophenone                                                                        trans-3-dimethylamino-4'-fluoroacrylo-                                                              96-97°                                             phenone                                                     14   1-Adamanyl methyl ketone                                                                     3-dimethylamino-1-tricyclo[3.3.1.1.sup.3,7 ]-                                                       142-143°                                           dec-1-yl-2-propen-1-one                                     15   4'-Acetylbiphenyl                                                                            3-dimethylamino-4'-phenylacrylophenone                                                                135-137.5°                    16   2'-Acetonaphthone                                                                            ( .sub.-- E)-3-dimethylamino-2'-acrylonaphthone                                                     96-98°                          17   3',4'-Dichloroacetophenone                                                                   trans-3',4'-dichloro-3-dimethylamino-                                                               94-95°                                             acrylophenone                                               18   3',4'-Dimethylacetophenone                                                                   3-dimethylamino-3' ,4'-dimethylacrylo-                                                              108-110°                                           phenone                                                     19   2',4'-Dichloroacetophenone                                                                   2',4'-Dichloro-3-dimethylaminoacrylo-                                                               83.5-85°                                           phenone                                                     20   2',6'-Difluoroacetophenone                                                                   1'-2',6'-difluorophenyl)-3-(dimethyl-                                                               67-69°                                             amino)-2-propen-1-one                                       21   2-Acetyl-4-methylthiophene                                                                   3-(dimethylamino)-1-(4-methyl-2-thienyl)-                                                           102-104°                                           2-propen-1-one                                              22   3-Acetyl-1-methylpyrrole                                                                     3-(dimethylamino)-1-(1-methyl-1H-pyrrol-                                                            123-125°                                           3-yl)-2-propen-1-one                                        23   2-Acetylthiophene                                                                            3-dimethylamino-1-(2-thienyl)-2-propen-1-                                                           114-115°                                           one                                                         24   2-Acetyl-3-methylthiophene                                                                   ( .sub.-- E)-3-dimethylamino-1-(3-methyl-2-                                                         45-49°                                             thienyl)-2-propen-1-one                                     25   2',4'-Difluoroacetophenone                                                                   3-dimethylamino-2',4'-difluoroacrylo-                                                               48-49°                                             phenone                                                     26   2',5'-Difluoroacetophenone                                                                   3-dimethylamino-2',5'-difluoroacrylophenone                                                         66-67°                          __________________________________________________________________________

EXAMPLE 27

A mixture of 58.1 g of (3-dimethylamino-1-(3-thienyl)-2-propen-1-one, 23.4 g of hydroxylamine hydrochloride and 250 ml of commercial absolute methanol is heated on a steam bath for 2 hours. The reaction is concentrated in vacuo, partitioned between methylene chloride and water and the organic layer dried over sodium sulfate. The methylene chloride is passed thru a short column of hydrous magnesium silicate and concentrated in vacuo to give 41.25 g (85%) of the desired product as a red-orange oil which solidified on standing. CI-MS: M/z 151(M⁺).

Using the general procedure of Example 27, the following compounds of Example 28-52, shown in Table II are prepared.

                  TABLE II                                                         ______________________________________                                               Starting                                                                 Exam- Material                                                                 ple   of Example                                                                               Compound        MP °C.                                  ______________________________________                                         28     2        5-Phenylisoxazole                                                                              Colorless liquid                               29     3        5-(5-Bromo-2-thienyl)-                                                                         66-68°                                                  isoxazole                                                      30     4        5-( -p-Chlorophenyl)-                                                                          84-85°                                                  isoxazole                                                      31     5        5-( -p-Methoxyphenyl)-                                                                         64-65°                                                  isoxazole                                                      32     6        5- -p-Tolylisoxazole                                                                           60-61°                                  33     7        5-(5-Methyl-2-thienyl)-                                                                        30-32°                                                  isoxazole                                                      34     8        5-(2-Furanyl)isoxazole                                                                         Pale yellow oil                                35     9        5-(5-Methyl-2-furanyl)-                                                                        32-33°                                                  isoxazole                                                      36    10        5-(3-Ethylphenyl)isoxa-                                                                        Colorless liquid                                               zole                                                           37    11        5-(4-Nitrophenyl)isoxa-                                                                        172-174°                                                zole                                                           38    12        5-(2-Fluorophenyl)isoxa-                                                                       Yellow liquid                                                  zole                                                           39    13        5-(4-Fluorophenyl)isoxa-                                                                       52-53°                                                  zole                                                           40    14        5-Tricyclo[3.3.1.1..sup.3,7 ]-                                                                 32-33°                                                  dec-1-yl-isoxazole                                             41    15        5-[1,1'-Biphenyl]-4-yl-                                                                        130-132°                                                isoxazole                                                      42    16        5-(2-Naphthalenyl)isoxa-                                                                       110-112°                                                zole                                                           43    17        5-(3,4-Dichlorophenyl)-                                                                        88-89°                                                  isoxazole                                                      44    18        5-(3,4-Dimethylphenyl)-                                                                        46-47°                                                  isoxazole                                                      45    19        5-(2,4-Dichlorophenyl)-                                                                        127-129°                                                isoxazole                                                      46    20        5-(2,6-Difluorophenyl)-                                                                        63-64°                                                  isoxazole                                                      47    21        5-(4-Methyl-2-thienyl)-                                                                        pale yellow liquid                                             isoxazole                                                      48    22        5-(1-Methyl-1 .sub.-- H-pyrrol-2-                                                              pale yellow liquid                                             yl)isoxazole                                                   49    23        5-(2-Thienyl)isoxazole                                                                         dark yellow-                                                                   orange liquid                                  50    24        5-(3-Methyl-2-thienyl)-                                                                        pale                                                           isoxazole       yellow liquid                                  51    25        5-(2,4-Difluorophenyl)-                                                                        64-66°                                                  isoxazole                                                      52    26        5-(2,5-Difluorophenyl)-                                                                        74-77°                                                  isoxazole                                                      ______________________________________                                    

EXAMPLE 53 α-[(Dimethylamino)methylene]-β-oxo-3-thiophenepropanenitrile

A mixture of 41.2 g of 5-(3-thienyl)isoxazole and 36.0 g of dimethylformamide dimethylacetal, under nitrogen, is heated on a steam bath for 4 hours. The reaction is concentrated in vacuo to give a viscous oil which solidified. The residue is dissolved in methylene chloride and passed thru a short column of hydrous magnesium silicate. On cooling, 31.76 g of the desired product is obtained, mp 118°-119°, CI-MS:m/z 206(M⁺). Concentrating in vacuo the methylene chloride gives an additional 20.2 g of product. (Total recovered 51.96 g, 92%).

Using the general procedure of Example 53, the following compounds of Example 54-78, shown in Table III are prepared.

                  TABLE III                                                        ______________________________________                                               Starting                                                                 Exam- Material                                                                 ple   of Example                                                                               Compound          MP °C.                                ______________________________________                                         54    28        2-Benzoyl-3-dimethylamino-                                                                       111-113°                                              acrylonitrile                                                  55    28        5-Bromo-α-[(dimethyl-                                                                      190-192°                                              amino)methylene]-β-oxo-2-                                                 thiophenepropanenitrile                                        56    29        2- -p-Chlorobenzoyl-3-                                                                           118-121°                                              dimethylaminoacryloni-                                                         trile                                                          57    30        α-[(Dimethylamino)methyl-                                                                  107-110°                                              ene]-4-methoxy-β-oxo-                                                                       (dec)                                                        benzenepropanenitrile                                          58    31        α-[(Dimethylamino)methyl-                                                                  132-135°                                              ene]-4-methyl-β-oxo-                                                      benzenepropanenitrile                                          59    32        α-[(Dimethylamino)methyl-                                                                  151-153°                                              ene]-5-methyl-β-oxo-2-                                                    thiophenepropanenitrile                                        60    33        α-[(Dimethylamino)methyl-                                                                  112-125°                                              ene]-β-oxo-2-furanpro-                                                    panenitrile                                                    61    34        α-[(Dimethylamino)methyl-                                                                  135-137°                                              ene]-5-methyl-β-oxo-2-                                                    furanpropanenitrile                                            62    35        α-[(Dimethylamino)methyl-                                                                  red-orange                                                   ene]-3-ethyl-β-oxo-                                                                         oil                                                          benzenepropanenitrile                                          63    36        α-[(Dimethylamino)methyl-                                                                  154-156°                                              ene]-4-nitro-β-oxo-                                                       benzenepropanenitrile                                          64    37        α-[(Dimethylamino)methyl-                                                                  62-74°                                                ene]-2-fluoro-β-oxo-                                                      benzenepropanenitrile                                          65    38        α-[ (Dimethylamino)methyl-                                                                 142-145°                                              ene]-4-fluoro-β-oxo-                                                      benzenepropanenitrile                                          66    39        α-[(Dimethylamino)methyl-                                                                  183-189°                                              ene]-β-oxo-tricyclo-                                                      [3.3.1.1..sup.3,7 ]decane-1-                                                   propanenitrile                                                 67    40        α-[(Dimethylamino)methyl-                                                                  174-176°                                              ene]-β-oxo-4-biphenyl-                                                    propionitrile                                                  68    41        α-[(Dimethylamino)methyl-                                                                  115-118°                                              ene]-β-oxo-2-naphthalene-                                                 propanenitrile                                                 69    42        3,4-Dichloro-α-[(dimethyl-                                                                 130-142°                                              amino)methylene]-β-oxo-                                                   benzenepropanenitrile                                          70    43        α-[(Dimethylamino)methyl-                                                                   82-112°                                              ene]-3,4-dimethyl-β-oxo-                                                  benzenepropanenitrile                                          71    44        2,4-Dichloro-α-[(dimethyl-                                                                 yellow glass                                                 amino)methylene]-β-oxo-                                                   benzenepropanenitrile                                          72    45        α-[(Dimethylamino)methyl-                                                                  109-111°                                              ene]-2,6-difluoro-β-oxo-                                                  benzenepropanenitrile                                          73    46        α-[(Dimethylamino)methyl-                                                                  127-132°                                              ene]-4-methyl-β-oxo-2-                                                    thiophenepropanetrile                                          74    47        α-[(Dimethylamino)methyl-                                                                   97-100°                                              ene]-1-methyl-β-oxo-1 .sub.-- H-                                          pyrrole-2-propanenitrile                                       75    48        α-[(Dimethylamino)methyl-                                                                  136-140°                                              ene]-β-oxo-2-thiophene-                                                   propanenitrile                                                 76    49        α-[(Dimethylamino)methyl-                                                                  red-brown                                                    ene]-3-methyl-β-oxo-2-                                                                      viscous syrup                                                thiophenepropanenitrile                                        77    50        α-[(Dimethylamino)methyl-                                                                  137-139°                                              ene]-2,4-difluoro-β-oxo-                                                  benzenepropanenitrile                                          78    51        α-[(Dimethylamino)methyl-                                                                  108-110°                                              ene]-2,5-difluoro-β-oxo-                                                  benzenepropanenitrile                                          ______________________________________                                     

We claim:
 1. A compound having the formula ##STR6## wherein R₁ is selected from the group consisting of 3-thienyl, 2-furanyl, 2-fluorophenyl, 4-fluorophenyl, 2,6-difluorophenyl, 2-thienyl, 2,4 difluorophenyl, 2,5 difluorophenyl.
 2. The compound according to claim 1, 5-(3-thienyl)isoxazole.
 3. The compound according to claim 1, 5-(2-furanyl)isoxazole.
 4. The compound according to claim 1, 5-(2-fluorophenyl)isoxazole.
 5. The compound according to claim 1, 5-(4-fluorophenyl)isoxazole.
 6. The compound according to claim 1, 5-(2,6-difluorophenyl)isoxazole.
 7. The compound according to claim 1, 5-(2-thienyl)isoxazole.
 8. The compound according to claim 1, 5-(2,4-difluorophenyl)isoxazole.
 9. The compound according to claim 1, 5-(2,5-difluorophenyl)isoxazole. 